Combined Superoxide Dismutase Mimetic and Peroxynitrite Scavenger Protects Against Neointima Formation After Endarterectomy in Association with Decreased Proliferation and Nitro-oxidative Stress

• Published in: European journal of vascular and endovascular surgery Vol. 40; no. 2; pp. 168 - 175
• Main Authors: Hirschberg, K, Radovits, T, Korkmaz, S, Loganathan, S, Zöllner, S, Seidel, B, Páli, S, Barnucz, E, Merkely, B, Karck, M, Szabó, G
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2010
• Subjects: Animals; Antioxidants; Carotid arteries; Carotid Stenosis - metabolism; Carotid Stenosis - prevention & control; Carotid Stenosis - surgery; Cell Proliferation - drug effects; Disease Models, Animal; Endarterectomy, Carotid; Free Radicals - pharmacology; Gene expression; Gene Expression Regulation - drug effects; Hyperplasia; Immunohistochemistry; In Situ Nick-End Labeling; Lipid Peroxidation; Male; Metalloporphyrins - pharmacology; Oxidative Stress - drug effects; Oxidative Stress - physiology; Peroxynitrite; Peroxynitrous Acid - metabolism; Rats; Rats, Sprague-Dawley; Restenosis; Scavenger Receptors, Class E; Secondary Prevention; Surgery; Tunica Intima - pathology; Restenosis; Antioxidants; Peroxynitrite; Gene expression; Carotid arteries
• ISSN: 1078-5884; 1532-2165
• DOI: 10.1016/j.ejvs.2010.03.024

Abstract Objective Reactive oxygen and nitrogen species (e.g., peroxynitrite) may trigger neointima formation leading to restenosis. In a rat carotid endarterectomy (CEA) model, we investigated the effects of the manganese(III)tetrakis(4-benzoic acid)porphyrin (MnTBAP), a superoxide dismutase (SOD) mimetic and peroxynitrite scavenger on neointima formation. Methods CEA was performed in male Sprague–Dawley rats. Animals received either vehicle (control group; n = 15) or 15 mg kg−1 day−1 MnTBAP intraperitoneally for 3 weeks (treatment group; n = 13). Four groups of carotids were analysed: the left, uninjured carotids (sham) and the right, injured carotids (control CEA) from the control group, the right, injured carotids from the treatment group (CEA + MnTBAP) and an additional group of carotids that were harvested 1 h following endarterectomy. The analysis of carotid arteries was performed by histology, immunohistochemistry and real-time polymerase chain reaction (PCR). Plasma malondialdehyde (MDA) levels were measured by lipid hydroperoxidase assay. Results Stenosis rate (10.5 ± 8.1% vs. 45.4 ± 28.3%), the percentage of proliferating cell nuclear antigen-positive cells (13.4 ± 7.1% vs. 23.3 ± 11.0%) and nitrotyrosine immunoreactivity (5.8 ± 1.9 vs. 8.0 ± 2.0) were significantly reduced in the vascular wall of the CEA + MnTBAP group compared with control CEA group. Ratio of Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL)-positive nuclei was significantly lower after antioxidant therapy (41.7 ± 26.7% vs. 64.9 ± 18.5%). Plasma MDA levels increased after endarterectomy (11.7 ± 4.8 vs. 4.1 ± 2.0 μmol l−1 ) and reduced in the treatment group (3.2 ± 2.1 μmol l−1 ). No significant gene regulation after MnTBAP treatment could be noted. Conclusions MnTBAP decreased neointima formation, which was associated with reduced vascular smooth muscle cell proliferation and attenuated local and systemic nitro-oxidative stress.